The present invention relates to novel methods and compositions comprising opioids and opioid antagonists. More particularly, the present invention relates to novel methods and compositions comprising opioids and peripheral mu opioid antagonist compounds.
It is well known that opioid drugs target three types of endogenous opioid receptors (i.e., mu, delta and kappa receptors) in biological systems. Most opioids, such as morphine, are mu opioid agonists that are often used as analgesics for the treatment of severe pain due to their activation of mu opioid receptors in the brain and central nervous system (CNS). Opioid receptors are, however, not limited to the CNS, and may be found in other tissues throughout the body. A number of side effects of opioid drugs may be caused by activation of these peripheral receptors. Administration of mu opioid agonists often results in intestinal dysfunction due to the large number of receptors in the wall of the gut (Wittert, G., Hope, P. and Pyle, D., Biochemical and Biophysical Research Communications 1996, 218, 877-881; Bagnol, D., Mansour, A., Akil, A. and Watson, S. J., Neuroscience 1997, 81, 579-591). Specifically, opioids are generally known to cause nausea and vomiting as well as inhibition of normal propulsive gastrointestinal function in animals and man (Reisine, T., and Pasternak, G., Goodman and Gilman""s The Pharmacological Basis of Therapeutics Ninth Edition 1996, 521-555) resulting in side effects such as, for example, constipation. It has been reported that acute nausea or vomiting may occur in up to about 33% of patients who receive oral narcotic analgesics and in up to about 80% of patients who receive injectable narcotics following surgery or trauma. This is due, at least in part, to direct effects of narcotics on the gastrointestinal (GI) tract.
Opioid-induced side effects, such as nausea, vomiting, and inhibited gastrointestinal propulsive activity remain serious problems for patients being administered opioid analgesics for both short term and long term pain management. Opioid antagonist compounds that do not readily cross the blood-brain barrier (peripherally acting drugs) have been tested for use in curbing opioid-induced side effects. For instance, the peripheral mu opioid antagonist compound methylnaltrexone and related compounds have been suggested for use in curbing opioid-induced side effects in patients. U.S. Pat. Nos. 5,972,954, 5,102,887, 4,861,781, and 4,719,215 disclose the use of methylnaltrexone and related compounds in controlling opioid-induced pruritus, nausea, and/or vomiting. Additionally, methylnaltrexone has been shown to effectively reduce the incidence of opioid-induced nausea and pruritus as disclosed by Yuan, C. -S. et al. Drug and Alcohol Dependence 1998, 52, 161. Similarly, U.S. Pat. Nos. 5,250,542, 5,434,171, 5,159,081, and 5,270,328, disclose peripherally selective piperidine-N-alkylcarboxylate opioid antagonists as being useful for the treatment of the opioid side effects constipation, nausea or vomiting, as well as irritable bowel syndrome and idiopathic constipation.
It is frequently the case that drugs have undesirable side effects, and patients taking such drugs are often prescribed additional drugs for countering these side effects. Thus, patients may be required to take multiple doses of different drugs, causing inconvenience and possible administration of incorrect doses. It may therefore be desirable for multiple drugs to be combined as one dose in a fixed ratio for ease of administration. Given that nausea, vomiting, and inhibited gastrointestinal propulsive activity are common side effects of opioid analgesics that contribute to the discomfort of a patient receiving such therapy, a need for a specific and effective side effect-relieving remedy is present. As it is not readily evident to combine two or more drugs for simultaneous administration, due to the complex nature of drug interactions which are often undesirable and even fatal to the patient, it is desirable to identify drug formulations that contain compounds when taken simultaneously in pre-measured, fixed-dose forms, resulting in safe alternative means for administering multiple drugs. In the present invention, it has been found that opioid analgesics, with their common undesirable side effects, are optimal candidates for such formulations in combination with peripheral mu opioid antagonist compounds. The methods and formulations of the present invention are directed toward these, as well as other, important ends.
Accordingly, the present invention is directed, in part, to novel methods and compositions for treating and/or preventing side effects that may be associated, for example, with the administration of opioids. Specifically, in one embodiment, there are provided methods of preventing or treating a side effect associated with an opioid comprising administering to a patient, in combination with an effective amount of an opioid, an effective amount of a compound of the following formula (I): 
wherein
R1 is hydrogen, alkyl or alkenyl;
R2 is hydrogen, alkyl or alkenyl;
R3 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl or aryl-substituted alkyl;
R4 is hydrogen, alkyl or alkenyl;
A is OR5 or NR6R7; wherein:
R5 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
R2 is hydrogen or alkyl;
R7 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl-substituted alkyl, aryl-substituted alkyl, or alkylene substitued B or, together with the nitrogen atom to which they are attached, R6 and R7 form a heterocyclic ring;
B is 
C(xe2x95x90O)W or NR8R9; wherein;
R8 is hydrogen or alkyl;
R9 is hydrogen, alkyl, alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl or aryl-substituted alkyl or, together with the nitrogen atom to which they are attached, R8 and R9 form a heterocyclic ring;
W is OR10, NR11R12, or OE; wherein
R10 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
R11 is hydrogen or alkyl;
R12 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aryl-substituted alkyl or alkylene substituted C(xe2x95x90O)Y or, together with the nitrogen atom to which they are attached, R11 and R12 form a heterocyclic ring;
E is 
alkylene substituted (Cxe2x95x90O)D, or xe2x80x94R13OC(xe2x95x90O)R14;
wherein
R13 is alkyl substituted alkylene;
R14 is alkyl;
D is OR15 or NR16R17;
wherein:
R15 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
R16 is hydrogen, alkyl, alkenyl, aryl, aryl-substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or cycloalkenyl-substituted alkyl;
R17 is hydrogen or alkyl or, together with the nitrogen atom to which they are attached, R16 and R17 form a heterocyclic ring;
Y is OR18 or NR19R20;
wherein:
R18 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
R19 is hydrogen or alkyl;
R20 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl or, together with the nitrogen atom to which they are attached, R19 and R20 form a heterocyclic ring;
R21 is hydrogen or alkyl; and
n is 0 to 4;
or a stereoisomer, prodrug, or pharmaceutically acceptable salt, hydrate or N-oxide thereof.
Another embodiment of the invention relates to methods of preventing or treating a side effect associated with an opioid comprising administering to a patient an effective amount of an opioid in combination with an effective amount of a peripheral mu opioid antagonist compound.
Still another embodiment of the invention relates to methods of treating or preventing pain comprising administering to a patient an effective amount of an opioid, in combination with an effective amount of a compound of the following formula (I): 
wherein:
R1 is hydrogen or alkyl;
R2 is hydrogen, alkyl or alkenyl;
R3 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl or aryl-substituted alkyl;
R4 is hydrogen, alkyl or alkenyl;
A is OR5 or NR6R7; wherein:
R5 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
R6 is hydrogen or alkyl;
R7 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl-substituted alkyl, aryl-substituted alkyl, or alkylene substitued B or, together with the nitrogen atom to which they are attached, R6 and R7 form a heterocyclic ring;
B is 
C(xe2x95x90O)W or NR8R9; wherein;
R8 is hydrogen or alkyl;
R9 is hydrogen, alkyl, alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl or aryl-substituted alkyl or, together with the nitrogen atom to which they are attached, R8 and R9 form a heterocyclic ring;
W is OR10, NR11R12, or OE; wherein
R10 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
R11 is hydrogen or alkyl;
R12 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aryl-substituted alkyl or alkylene substituted C(xe2x95x90O)Y or, together with the nitrogen atom to which they are attached, R11 and R12 form a heterocyclic ring;
E is 
alkylene substituted (Cxe2x95x90O)D, or xe2x80x94R13OC(xe2x80x94O)R14;
wherein
R13 is alkyl substituted alkylene;
R14 is alkyl;
D is OR15 or NR16R17;
wherein:
R15 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
R16 is hydrogen, alkyl, alkenyl, aryl, aryl-substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or cycloalkenyl-substituted alkyl;
R17 is hydrogen or alkyl or, together with the nitrogen atom to which they are attached, R16 and R17 form a heterocyclic ring;
Y is OR18 or NR19R20;
wherein:
R18 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
R19 is hydrogen or alkyl;
R20 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl or, together with the nitrogen atom to which they are attached, R19 and R20 form a heterocyclic ring;
R21 is hydrogen or alkyl; and
n is 0 to 4;
or a stereoisomer, prodrug, or pharmaceutically acceptable salt, hydrate or N-oxide thereof.
Yet another embodiment of the invention relates to methods of treating or preventing pain comprising administering to a patient an effective amount of an opioid in combination with an effective amount of a peripheral mu opioid antagonist compound.
In another embodiment of the invention, there are provided pharmaceutical compositions comprising an effective amount of an opioid and an effective amount of a compound of the following formula (I): 
wherein:
R1 is hydrogen or alkyl;
R2 is hydrogen, alkyl or alkenyl;
R3 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl or aryl-substituted alkyl;
R4 is hydrogen, alkyl or alkenyl;
A is OR5 or NR6R7; wherein:
R5 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
R6 is hydrogen or alkyl;
R7 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl-substituted alkyl, aryl-substituted alkyl, or alkylene substitued B or, together with the nitrogen atom to which they are attached, R6 and R7 form a heterocyclic ring;
B is 
C(xe2x95x90O)W or NR8R9; wherein;
R8 is hydrogen or alkyl;
R9 is hydrogen, alkyl, alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl or aryl-substituted alkyl or, together with the nitrogen atom to which they are attached, R8 and R9 form a heterocyclic ring;
W is OR10, NR11R12, or OE; wherein
R10 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
R11 is hydrogen or alkyl;
R12 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aryl-substituted alkyl or alkylene substituted C(xe2x95x90O)Y or, together with the nitrogen atom to which they are attached, R11 and R12 form a heterocyclic ring;
E is 
alkylene substituted (Cxe2x95x90O)D, or xe2x80x94R13OC(xe2x95x90O)R14;
wherein
R13 is alkyl substituted alkylene;
R14 is alkyl;
D is OR15 or NR16R17;
wherein:
R15 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
R16 is hydrogen, alkyl, alkenyl, aryl, aryl-substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or cycloalkenyl-substituled alkyl;
R17 is hydrogen or alkyl or, together with the nitrogen atom to which they are attached, R16 and R17 form a heterocyclic ring;
Y is OR18 or NR19R20;
wherein:
R18 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
R19 is hydrogen or alkyl;
R20 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl or, together with the nitrogen atom to which they are attached, R19 and R20 form a heterocyclic ring;
R21 is hydrogen or alkyl; and
n is 0 to 4;
or a stereoisomer, prodrug, or pharmaceutically acceptable salt, hydrate or N-oxide thereof.
Still another embodiment of the invention relates to pharmaceutical compositions comprising an effective amount of an opioid, an effective amount of a peripheral mu opioid antagonist, and a pharmaceutically acceptable carrier.
Yet another embodiment of the invention relates to pharmaceutical kits comprising one or more containers containing pharmaceutical dosage units comprising an effective amount of an opioid and an effective amount of a compound of the following formula (I): 
wherein:
R1 is hydrogen or alkyl;
R2 is hydrogen, alkyl or alkenyl;
R3 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl or aryl-substituted alkyl;
R4 is hydrogen, alkyl or alkenyl;
A is OR5 or NR6R7; wherein:
R5 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
R6 is hydrogen or alkyl;
R7is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl-substituted alkyl, aryl-substituted alkyl, or alkylene substitued B or, together with the nitrogen atom to which they are attached, R6 and R7 form a heterocyclic ring;
B is 
C(xe2x95x90O)W or NR8R9; wherein;
R8 is hydrogen or alkyl;
R9 is hydrogen, alkyl, alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl or aryl-substituted alkyl or, together with the nitrogen atom to which they are attached, R8 and R9 form a heterocyclic ring;
W is OR10, NR11R12, or OE; wherein
R10 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
R11 is hydrogen or alkyl;
R12 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aryl-substituted alkyl or alkylene substituted C(xe2x95x90O)Y or, together with the nitrogen atom to which they are attached, R11 and R12 form a heterocyclic ring;
E is 
alkylene substituted (Cxe2x95x90O)D, or xe2x80x94R13OC(xe2x95x90O)R14;
wherein
R13 is alkyl substituted alkylene;
R14 is alkyl;
D is OR15 or NR16R17;
wherein:
R15 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
R16 is hydrogen, alkyl, alkenyl, aryl, aryl-substituted alkyl, cycloalkyl, cycloalkenyt, cycloalkyl-substituted alkyl or cycloalkenyl-substituted alkyl;
R17 is hydrogen or alkyl or, together with the nitrogen atom to which they are attached, R16 and R17 form a heterocyclic ring;
Y is OR18 or NR19R20;
wherein:
R18 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
R19 is hydrogen or alkyl;
R20 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl or, together with the nitrogen atom to which they are attached, R19 and R20 form a heterocyclic ring;
R21 is hydrogen or alkyl; and
n is 0 to 4;
or a stereoisomer, prodrug, or pharmaceutically acceptable salt, hydrate or N-oxide thereof.
Still another embodiment of the invention relates to pharmaceutical kits comprising one or more containers containing pharmaceutical dosage units comprising an effective amount of an opioid and an effective amount of a peripheral mu opioid antagonist.
These and other aspects of the invention will become more apparent from the following detailed description.